Percutaneous Transcatheter Mitral Valve Repair

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 4, NO. 1, 2011 2011 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 1936-8798/$36.00 PUBLISHED BY ELSEVIER INC. DOI: 10.1016/j.jcin.2010.09.023 STATE-OF-THE-ART PAPER Percutaneous Transcatheter Mitral Valve Repair A Classification of the Technology Paul T. L. Chiam, MBBS,* Carlos E. Ruiz, MD, PHD Singapore; and New York, New York Surgical treatment of mitral regurgitation (MR) has evolved from mitral valve replacement (MVR) to repair (MVR e ), because MVR e produces superior long-term outcomes. In addition, MVR e can be achieved through minimally invasive approaches. This desire for less invasive approaches coupled with the fact that a significant proportion of patients especially elderly persons or those with significant comorbidities or severe left ventricular (LV) dysfunction, are not referred for surgery, has driven the field of percutaneous MVR e. Various technologies have emerged and are at different stages of investigation. A classification of percutaneous MVR e technologies on the basis of functional anatomy is proposed that groups the devices into those targeting the leaflets (percutaneous leaflet plication, percutaneous leaflet coaptation, percutaneous leaflet ablation), the annulus (indirect: coronary sinus approach or an asymmetrical approach; direct: true percutaneous or a hybrid approach), the chordae (percutaneous chordal implantation), or the LV (percutaneous LV remodeling). The percutaneous edge-to-edge repair technology has been shown to be noninferior to open repair in a randomized clinical trial (EVER- EST II [Endovascular Valve Edge-to-Edge REpair Study]). Several other technologies employing the concepts of direct and indirect annuloplasty and LV remodeling have achieved first-in-man results. Most likely a combination of these technologies will be required for satisfactory MVR e. However, MVR e is not possible for many patients, and MVR will be required. Surgical MVR is the standard of care in such patients, although percutaneous options are under development. (J Am Coll Cardiol Intv 2011;4:1 13) 2011 by the American College of Cardiology Foundation Mitral regurgitation (MR) is a common valvular abnormality, being present in 24% of adults with valvular heart disease and in 7% of the population 75 years of age (1,2). Surgical intervention is recommended for symptomatic severe MR or asymptomatic severe MR with left ventricular (LV) dysfunction or enlargement (3). Treatment of severe degenerative MR has evolved from mitral valve replacement (MVR) to mitral valve repair (MVR e )(3), because repair produces superior outcomes (4,5). For functional MR, however, the benefit of repair over MVR is less certain (6) From the *Department of Cardiology, National Heart Centre, Singapore, Singapore; and the Department of Cardiac and Vascular Interventional Services, Lenox Hill Heart and Vascular Institute of New York, New York, New York. Dr. Chiam reports that he has no relationships to disclose. Dr. Ruiz is a consultant for CoreValve. Manuscript received June 14, 2010; revised manuscript received September 8, 2010, accepted September 17, 2010. With increased understanding of the heterogenic pathophysiology of MR, cardiac surgeons have developed various techniques that increase the likelihood of successful repair (7). Mitral valve repair can also be achieved through minimally invasive approaches (8,9). This desire for less invasive approaches coupled with the fact that a significant proportion of patients especially elderly persons or those with significant comorbidities or severe LV dysfunction are not referred for surgery (10) has driven the field of percutaneous MVR e. Various technologies have emerged and are at different stages of investigation. Percutaneous Approaches to Mitral Valve (MV) Therapies The MV is just one of the elements of the mitral apparatus, and as such pathologies affecting the

2 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 1, 2011 annulus (mitral annulus [MA]), leaflets, papillary muscle, chordae tendineae, LV, and left atrium (LA) can all produce or contribute to MR. The functional anatomy and classification of MR have been reviewed recently (7) and would not be further discussed. Surgical techniques are primarily aimed at correcting the culprit mechanism(s) (e.g., prolapsed leaflet, annular dilation) that lead to MR (7), and a combination of techniques may be used to obtain the best outcome. These surgical techniques can be broadly classified into those aimed at the leaflets, MA, commissures, chordae, papillary muscles, and LV. Current percutaneous technologies for MVR e have been developed on the basis of some of these surgical principles. These technologies have been previously grouped into those acting on the leaflets, direct annuloplasty or indirect annuloplasty (via the coronary sinus [CS]), and chamber (LV) remodeling (11 15). A modified classification of percutaneous MVR e technology according to functional anatomy and device action is proposed (Table 1). This might facilitate more precise description of the current devices Abbreviations and Acronyms and accommodate emerging technologies. CS coronary sinus FIM first-in-man LA left atrium LV left ventricle MA mitral annulus MR mitral regurgitation MS mitral stenosis MV mitral valve MVR mitral valve replacement MVR e mitral valve repair Percutaneous Leaflet Plication (Edge-to-Edge Leaflet Repair) Principle. The leaflet plication technology is based on the surgical Alfieri technique (16), which brings the anterior and posterior leaflets together with a suture, creating a double orifice MV. This re-establishes leaflet coaptation, thereby reducing MR. This technique is most suitable for degenerative MR, although it could be employed in functional MR. Devices. The MitraClip (Abbott Vascular, Santa Clara, California) system uses a steerable catheter to deliver a clip to the anterior leaflet and posterior leaflet via transseptal access (Fig. 1). The safety and feasibility study (EVEREST I [Endovascular Valve Edge-to-Edge REpair Study]) (17) showed that, in 107 patients, procedural success (post-procedure MR 2 ) was achieved in 74% with 1% in-hospital mortality (17). At 1-year, freedom from death, MV surgery or MR 2 was 66%. Freedom from death and freedom from surgery were 90.1% and 76.3% at 3 years, respectively. No clip embolized, although partial clip detachment occurred in 10 patients (9%). Subsequently, 32 patients required surgery for MR; repair when planned was possible in 84%, demonstrating that surgical options were preserved (17,18). Data from the EVEREST II study, randomizing Mitra- Clip versus surgical repair, were recently presented (American College of Cardiology 2010). Patients (n 279) with symptomatic severe MR or asymptomatic severe MR with LV dysfunction were randomized in a 2:1 (device: surgery) fashion. Freedom from combined end point of death, MV surgery or reoperation 90 days after index procedure, and MR 2 at 1 year was 72.4% and 87.8% in the device and surgical groups, respectively, meeting the noninferiority hypothesis. The safety end point (all predefined adverse events plus blood transfusions 2 U) was superior in the device group (9.6% vs. 57% for surgery). The MitraClip thus seems to be an alternative option for selected patients. The Mobius device (Edwards Life Sciences, Irving, California) used a suture to create a double orifice MV. Despite feasibility in the animal model, initial human experience was limited by suture dehiscence and technical difficulties (19), and the program has been abandoned. The MitraFlex (TransCardiac Therapeutics, Atlanta, Georgia), which deploys a clip to the leaflets via the transapical route, is undergoing pre-clinical testing (this device also allows an artificial chord to be implanted during the same procedure). Limitations. The major limitation of this percutaneous technology is that the surgical Alfieri technique is typically used with an annuloplasty, because results without annuloplasty have been suboptimal with significant rates of recurrent MR and need for reoperation (20), especially in ischemic MR (21) or if annular calcification is present (20). However, in a small group of well-selected patients, 90% freedom from recurrent MR 2 or reoperation at 5 years could be achieved (22). Another limitation is the possibility of causing iatrogenic mitral stenosis (MS) (7), although Herrmann et al. (23) reported no significant stenosis in 96 patients with successful MitraClip(s) implanted. Leaflet Ablation Principle. Radiofrequency energy is delivered to the leaflet(s) to effect structural (fibrosis) or functional (reduced motion) alteration. This technology is designed to target degenerative MR. Device. The Thermocool irrigation ablation electrode (Biosense Webster, Inc., Diamond Bar, California) is a radiofrequency ablation (RFA) catheter that is delivered via femoral artery access retrograde into the LV. The catheter is placed in contact with the anterior leaflet, and RFA is delivered, causing scarring and fibrosis and reduced leaflet motion. Proof-ofconcept was demonstrated in an animal study (24). Limitations. Scarring and fibrosis from the RFA might not be precise, resulting in too-long or too-short post-ablation leaflet with residual or even worsening MR. Leaflet perforation and damage to adjacent cardiac structures might occur.

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 1, 2011 3 Table 1. Percutaneous MVR e and MVR Technologies Site of Action Mechanism of Action Device Status Major Limitations Percutaneous MVR e Technologies Leaflets Edge-to-edge (leaflet plication) MitraClip Randomized trial data presented Results when performed alone may not be durable. Possibility of iatrogenic MS. MitraFlex Pre-clinical development As for MitraClip Annulus Space occupier (leaflet coaptation) Percu-Pro Phase 1 trial Device thrombus formation. Residual MR or iatrogenic MS. Leaflet ablation Thermocool Animal models Scarring not precise with residual MR. Leaflet/cardiac structure perforation. Indirect annuloplasty Coronary sinus approach (CS reshaping) Monarc Carillon Viacor FIM results. Feasibility study ongoing. FIM results. Feasibility study complete. FIM results. Feasibility study ongoing. CS at a distance from MA. Possibility of coronary artery compression. As above As above Asymmetrical approach St. Jude device Animal models CS at a distance from MA. Unequal tension on LA or MA. Device fracture or erosion, and thrombus formation. NIH-Cerclage technology Animal models CS at a distance from MA. Unequal tension on LA or MA. Direct annuloplasty Percutaneous mechanical Mitralign FIM results Only posterior MA cinching. cinching Accucinch GDS FIM results As above Millipede ring system Pre-clinical development Feasibility and stability of fixation unknown Percutaneous energymediated QuantumCor Animal models Scarring not precise. Possible residual MR or cinching iatrogenic MS. Risk of cardiac structure perforation. ReCor Pre-clinical development As above Hybrid Mitral solutions Pre-clinical development Not true percutaneous technique MiCardia Pre-clinical development As above Chordal implants Transapical Artificial chord Neochord, MitraFlex Pre-clinical development Residual leaflet prolapse or restriction with residual MR. Thrombus formation. Transapical-Transseptal Artificial chord Babic Pre-clinical development As above LV LV (and MA) remodeling Mardil-BACE Temporary human implant Requires mini-thoracotomy. Long-term effects unknown. Percutaneous MVR Technologies Valve implants Right mini-thoracotomy Endovalve-Herrmann prosthesis Animal models Anchoring challenges. LV outflow obstruction. Paravalvular leaks. Transapical Lutter prosthesis Animal models As above Transseptal CardiaQ prosthesis Pre-clinical development As above CS coronary sinus; FIM first-in-man; LV left ventricle/ventricular; MA mitral annulus; MR mitral regurgitation; MS mitral stenosis; MVR mitral valve replacement; MVR e mitral valve repair; NIH National Institutes of Health. Leaflet Space Occupier Principle. A device acting like a buoy is positioned across the MV orifice to provide a surface against which the leaflets can coapt, reducing MR. This could be applied to degenerative or functional MR. Device. The Percu-Pro device (Cardiosolutions, Stoughton, Massachusetts) consists of a polyurethane-silicone polymer space-occupying buoy that is anchored at the apex through the MV (Fig. 2) acting as a spacer in the mitral orifice. A transseptal approach is required to implant the anchor in the apex. It is undergoing phase 1 trial. Limitations. Possible limitations are thrombus formation on the device, residual MR, or iatrogenic MS (restricted inflow by the spacer ).

4 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 1, 2011 Figure 1. MitraClip Device Picture of the MitraClip device (left), the MitraClip deployed on the mitral valve leaflets (middle), and the tissue bridge with a double-orifice mitral valve (right). Annuloplasty Indirect This approach mimics surgical annuloplasty rings, which are commonly used for repair of both degenerative and functional MR. Because surgical annuloplasty necessitates cardiac bypass, it is usually performed with another indication such as coronary artery bypass graft (25). The percutaneous devices might thus offer an alternative for those at excessive surgical-risk or who do not require another concomitant cardiac surgical procedure. Several percutaneous devices are in clinical testing, mainly for functional MR. CS Approach (CS Reshaping) Principle. This approach involves implantation of devices within the CS with the aim of pushing the posterior annulus anteriorly, thereby reducing the septal-lateral (anterior-posterior) dimension of the MA. This has been demonstrated in surgical data to improve leaflet coaptation and decrease MR (26). Devices. The Monarc (previously Viking) system (Fig. 3) (Edwards Lifesciences) consists of an outer guide catheter, a smaller delivery catheter, and a nitinol implant. The implant has 3 sections: distal and proximal self-expanding anchors, and a springlike bridge that has shortening forces. This draws the proximal CS and distal great cardiac vein closer, indirectly displacing the posterior annulus anteriorly. The Viking device produced an initial favorable effect on MR, although device fracture and recurrence of MR occurred, and the feasibility study was stopped (27). The re-engineered device (Monarc) has a reinforced bridge segment. The phase 1 trial (Evolution) of functional MR with the Monarc device demonstrated implantation success in 82% (59 of 72 patients), with 13 failures (18%) due to tortuous anatomy or inappropriate CS dimensions. Three myocardial infarctions occurred due to coronary artery compression (1 received coronary stenting, 1 treated medically, 1 fatality). Event-free survival was 81%, 72%, and 64% at 1 year and 2 and 3 years, respectively (Jan Harnek, European Society of Cardiology Congress 2010, Stockholm, Sweden). A larger Evolution II study is ongoing. The Carillon Mitral Contour System (Cardiac Dimension, Inc., Kirkland, Washington) (Fig. 4) consists of self-expandable nitinol distal and proximal anchors connected by a nitinol bridge that are placed in the great cardiac vein and proximal CS via a catheter-based system. Tension applied on the system results in cinching of the posterior periannular tissue and deflection of the Figure 2. Percu-Pro Device Diagram showing transseptal implantation of the Percu-Pro (Cardiosolutions, Stoughton, Massachusetts) spacer (left, middle), and the spacer providing a surface for leaflet coaptation (right).

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 1, 2011 5 Figure 3. Monarc Device device fracture, 3 underwent surgical annuloplasty, 1 died 3 months after implant) (30). Limitations. There are major limitations to the use of CS reshaping. The technique exploits the proximity of the CS to the MA. However, surgical anatomy suggests that the CS is located behind the LA wall at a significant distance from the MA (31,32). The projection of CS annuloplasty covered just over one-half of the total MA perimeter (32). Similarly with computed tomography angiography, there was significant variability in the relation of the CS to MA, and this distance was increased in severe MR with annular dilation (33,34). These CS devices likely shrink the MA only indirectly by traction on the LA wall. The annulus might in fact continue to dilate, reducing device effectiveness. Furthermore, there is a risk that these devices might compress a coronary artery. It has been demonstrated that a diagonal or ramus branch crossed between the CS and MA in 16% of patients, whereas it was between 64% and 80% for the left circumflex artery (31 34). Therefore, anatomic assessment of the CS, coronary artery, and MA relationship is mandatory before considering these devices. Other limitations include significant MA calcification, presence of CS pacing leads, coronary venous branch point variability, coronary venous system size constraints (risk of CS perforation), and structural leaflet abnormalities. This approach might theoretically jeopardize future attempts at implanting cardiac resynchro- The Monarc (Edwards Life Sciences, Irving, California) device (top) comprising proximal (larger) and distal anchors and a bridge, and diagrammatical representation after implantation in the coronary sinus. posterior MA anteriorly. A feasibility study showed modestly reduced septal-lateral dimension and MR when placed temporarily (28). Slippage of the anchors occurred, requiring device modification. Data from the AMADEUS trial (CARILLON Mitral Annuloplasty Device European Union Study) using the modified CARILLON XE device (Cardiac Dimension, Inc.) in functional MR due to dilated cardiomyopathy demonstrated implantation success in 62% (30 of 48 patients), with mean 1 grade reduction of MR (although it is uncertain whether this would be clinically meaningful). Implantation could not be achieved in 18 patients (38%) due to access issues (CS dissection/ perforation), insufficient MR reduction, and coronary artery compression. Coronary arteries were crossed frequently (36 of 43 implant attempts), although device was recaptured in only 17% where compromise was significant (29). The Viacor percutaneous transvenous mitral annuloplasty device (Viacor, Inc., Wilmington, Massachusetts) (Fig. 5) uses nitinol rods of varying length and stiffness, delivered via a catheter to the CS. This exerts outward force resulting in anterior displacement of the posterior annulus. Temporary human implantation was feasible. Subsequent permanent implantation was achieved although successful only in a small proportion (9 of 27 patients) (30). Problems encountered were access issues, unsuccessful MR reduction, unstable device, and technical delivery difficulties. During the study, the device remained in only 4 patients (17%) (1 Figure 4. Carillon XE Device The Carillon XE (Cardiac Dimension, Inc., Kirkland, Washington) device (top), comprising proximal (larger) and distal anchors and a bridge. Sequence of implantation with the delivery sheath in the coronary sinus (middle left), removal of sheath (middle right, bottom left), and only device remaining (bottom right).

6 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 1, 2011 Figure 5. Viacor Device The Viacor (Viacor, Inc., Wilmington, Massachusetts) PTMA rods (top left), access to the coronary sinus (bottom left), introduction of the rods (top right), and after full implantation of the rods (bottom right) in the coronary sinus. nization devices, although initial experience has been reassuring (35). Asymmetrical Approach Principle. This group of devices uses the proximity of the CS to the annulus to try to reshape the MA but in addition exert traction force on another portion of the LA or right atrium, resulting in asymmetrical forces. The aim is to reduce septal-lateral dimension and decrease MR. Devices. The percutaneous septal sinus shortening (PS 3 ) system (Ample Medical, Foster City, California) employed a CS anchor positioned behind posterior leaflet, a bridge (cinching wire) connecting the CS anchor to an atrial septal anchor (Amplatzer PFO occluder [AGA Medical, Plymouth, Minnesota]). Tension on the bridge reduced septal-lateral dimension and reduced MR (36). Further device development, however, has been abandoned. Another device by St. Jude Medical (Minneapolis, Minnesota) (Fig. 6) implanted in animal models consists of 4 helical anchors, 2 loading spacers, a tether rope, and a locking mechanism. The distal pair of anchors is delivered via the CS into the LV myocardium near the posterior leaflet scallop. The proximal pair is implanted via the right atrium into the postero-medial trigone. The 2 pairs of anchors are connected by a cable to effect cinching of the postero-medial MA. Dynamic shortening can be performed manually and reversibly, and the locking mechanism is a self-retracting, nitinol structure that maintains cinched load (37). The National Institutes of Health cerclage technology directs a guidewire via the CS into the first septal perforator of the great cardiac vein and, under imaging, across the myocardium to re-enter a right heart chamber. It is ensnared and exchanged for a suture and tension-fixation device. Initial animal models have proved promising with success in reducing MR (38). Limitations. The major drawbacks of this technology are: 1) the CS might not be in the same plane as the MA (true annuloplasty might not take place); and 2) unequal tension exerted on the CS or LA, with unknown long-term consequences. There is a theoretical risk of device erosion or fracture and possible thrombus formation on the connecting cable. Annuloplasty Direct: Percutaneous Mechanical Cinching Approach Principle. This technology reshapes the MA directly without using the CS, approaching the MA from the LV or the LA side. Sutures or some other device are implanted onto the MA itself and used to directly cinch the MA. These technologies might be able to address the potential limitations of the indirect annuloplasty method and would be most useful for functional MR (although it could be employed in degenerative MR). Devices. The Mitralign device (Mitralign, Tewksbury, Massachusetts) (Fig. 7) gains access to the annulus from the transventricular approach. Anchors are placed directly on the posterior MA and connected with a suture, creating a purse-string to

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 1, 2011 7 The ReCor (ReCor, Paris, France) device delivers highintensity focused ultrasound circumferentially and perpendicularly to the catheter shaft to induce tissue heating and collagen (and thus MA) shrinkage. Limitations. The limitation of the Mitralign and Accucinch devices is that only the posterior MA is cinched. Optimal surgical correction is currently thought to be obtained by performing an annuloplasty with a complete rather than a partial ring (32), because the intertrigonal distance is not fixed as previously believed (7). The Millipede system overcomes this issue, but feasibility and stability of annular fixation is unknown. Scarring induced by the QuantumCor and Recor devices might not be precisely controlled, and over-constriction with resultant MS or under-correction with residual MR could conceivably occur. Damage or perforation of neighboring cardiac structures including the CS is possible, although this was not observed in animal models (39). Annuloplasty Direct: Hybrid Approach Figure 6. St. Jude Device The St. Jude Medical device (St. Jude Medical, Minneapolis, Minnesota) (bottom left arrow denotes distal anchors near P2, bottom right arrow denotes proximal anchors near the postero-medial trigone). cinch the MA. Retrograde LV access to the periannular space has been achieved reliably with successful first-in-man (FIM) results (unpublished data). The Accucinch Annuloplasty System (Guided Delivery Systems, Santa Clara, California) uses a transventricular approach and has FIM results (unpublished data). The posterior annulus is cinched circumferentially from trigone to trigone (Fig. 8), with improvement in MR. The Millipede system (Millipede, LLC, Ann Arbor, Michigan) involves placement of a novel repositionable and retrievable annular ring with a unique attachment system via percutaneous (transseptal) or minimally invasive methods. Annuloplasty Direct: Percutaneous Energy-Mediated Cinching Approach Principle. Heat energy is applied to the MA, causing scarring and shrinkage of the MA. Devices. By the transatrial (transseptal) route, the QuantumCor (QuantumCor, Lake Forest, California) device (Fig. 9) effects direct annuloplasty by use of radiofrequency energy to cause scarring and constriction of the MA. It has a loop tip that contains electrodes and thermocouples to regulate the amount of energy delivered. This device has been tested in animal models with reduction of MA distances and nonischemic MR (39). Principle. An annuloplasty ring is implanted surgically and can be subsequently adjusted via transseptal access if MR recurs or worsens. Devices. The Adjustable Annuloplasty Ring (MitralSolutions, Fort Lauderdale, Florida) (Fig. 10) is implanted surgically and can be adjusted with a mechanical rotating cable, whereas the Dynamic annuloplasty Ring System (MiCardia, Inc., Irving, California), which recently had FIM results, is adjusted with radiofrequency energy. Limitations. Although this approach seems an effective way of customizing device size-shape to each patient under real-life loading conditions, initial surgical implantation is required. Therefore, these technologies are more of a hybrid technique. It is conceivable that they might evolve into true percutaneous technologies. Both are in pre-clinical development. Chordal Implantation Principle. Synthetic chords or sutures are implanted either from a transapical or transseptal approach and anchored onto the LV myocardium at one end, with the leaflet at the other. The length of the chord is then adjusted to achieve optimal leaflet coaptation and reduce MR. This approach would be mainly for degenerative MR. Devices. There are 3 devices currently in development: the transapically delivered MitraFlex (TransCardiac Therapeutics) and NeoChord (Neochord, Inc., Minnetonka, Minnesota) devices, and the transapical-transseptal route of the Babic device (Fig. 11). The MitraFlex and Neochord devices place an anchor in the inner LV myocardium and another on the leaflet via a transapical approach and connect the 2 with a synthetic chord. In the Babic device, 2 continuous suture tracks are created from the LV puncture

8 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 1, 2011 Figure 7. Mitralign Device Figures showing the Mitralign device (Mitralign, Tewksbury, Massachusetts) gaining access via the left ventricle (top left), placement of anchors on the posterior mitral annulus (top right, bottom left), and after cinching (bottom right). Figure 8. Accucinch Annuloplasty System Figure (left) showing action of the Accucinch device (Guided Delivery Systems, Santa Clara, California) and animal model (right) of the deployed Accucinch system (arrows denote suture along the posterior annulus).

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 1, 2011 9 Figure 9. QuantumCor Device The QuantumCor device (QuantumCor, Lake Forest, California) (left) and device applied to the mitral annulus via the transseptal approach (right). site through the puncture of the target leaflet and are exteriorized via the transseptal route. A pledget is apposed onto the exteriorized venous sutures and anchored onto the atrial side of the leaflet by retracting the guiding sutures from the epicardial end. A polymer tube is then interposed between the leaflet and free myocardial wall and secured at the epicardial surface by an adjustable knob. Limitations. Possible problems that might be encountered with this technology are residual leaflet prolapse (artificial chords too long) or leaflet restriction (chords too short) and residual MR (7) and device thrombus formation. LV Remodeling Principle. A device is used to reduce the anterior posterior dimension of the LV. This indirectly decreases the septallateral annular distance and also brings the LV papillary Figure 10. Adjustable Annuloplasty Ring System The Adjustable Annuloplasty Ring (MitralSolutions, Fort Lauderdale, Florida) (top left); the connecting cable (top right). The cable connected to the ring (bottom).

10 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 1, 2011 Figure 11. Transcatheter Chordal Implants The MitraFlex device sheath (TransCardiac Therapeutics, Atlanta, Georgia) (top left), clip for leaflet plication (top middle), and artificial chord implantation (top right); the NeoChord device (Neochord, Inc., Minnetonka, Minnesota) implanted from a transapical approach (middle); the Babic device (bottom). muscles closer to the leaflets. This approach seems suitable mainly for functional MR due to ischemic or cardiomyopathic etiologies. The percutaneous icoapsys technology was based on the Coapsys surgical system (Myocor, Maple Grove, Minnesota), which places pads on either side of the LV with a cord passing through the LV cavity to apply tension to the MA and basal LV wall, moving the posterior leaflet to better coapt with the anterior leaflet. Surgical data demonstrated implantation safety, reduction in MR, and positive LV remodeling (40). Although transpericardial percutaneous device implantation via a sub-xiphoid approach was feasible in animal models (41), device development has been discontinued. The Mardil-BACE (Mardil, Inc., Morrisville, North Carolina) (Fig. 12) device requires a mini-thoracotomy but is implanted on a beating heart. A silicone band is placed around the atrioventricular groove with built-in inflatable chambers placed on the MA. This reshapes the MA for better leaflet coaptation and can be remotely adjusted after implantation. No coronary artery compromise was shown in animal models, and proof-of-concept was demonstrated in 15 patients, although no further details were made available (unpublished data).

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 1, 2011 11 Figure 12. Mardil-BACE Device The Mardil-BACE device (Mardil, Inc., Morrisville, North Carolina) consists of a silicone band with inflatable chambers implanted around the atrioventricular groove. Limitations. There are sparse clinical data, and longer-term outcomes and adverse events are unknown. Target Patient Populations Despite the enthusiasm generated by these emerging devices, it is important to consider what patient populations are suitable for these technologies. The 2 etiologies of MR most amenable to surgical repair are degenerative and functional. Annuloplasty is the main technique used in functional MR, whereas leaflet repair is also usually performed in degenerative MR. In the EuroHeart survey, degenerative and functional etiologies accounted for 61% and 7%, respectively (2). From a global perspective, however, rheumatic disease (which has a low probability of repair) will take on greater prominence (up to 50%) (42). Despite numerous surgical techniques and performance under direct vision, repair was performed in just under one-half of patients with MR who required surgery in the U.S. and Europe (2,43), with unfavorable anatomy, absence of surgical expertise, and failure of conservative surgery being the major reasons (2). In addition, certain pathologies (rheumatic, endocarditic, inflammatory, and so forth) are often not repairable. Therefore, current percutaneous options might be useful only in a selected patient pool. The need for a cautious approach to percutaneous MVR e is further emphasized by the excellent results of surgical repair and the low perioperative mortality (44). Percutaneous MVR A combination of percutaneous techniques will most likely be needed if results comparable to surgery are expected. Despite the armamentarium available to surgeons and the increasing preference for repair, in a significant proportion Figure 13. Endovalve-Herrmann Prosthesis The Endovalve-Herrmann prosthesis (top right), loaded in the delivery sheath (top left), and sequence of implantation (bottom left and right).

12 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 1, 2011 Figure 14. CardiAQ Prosthesis The CardiAQ (CardiAQ Valve Technologies, Inc., Winchester, Massachusetts) prosthesis; this device is delivered transseptally (left) and locks onto the inferior (middle) and superior (right) surfaces of the mitral annulus. of patients, surgical MVR e is not possible or fails, and MVR is required (45). In the future, the novel technology of percutaneous MVR might become a possible alternative in a selected group of patients with a low probability of successful repair. However, the challenges are formidable. The MA has an asymmetrical saddle shape, and different anchoring designs might be required for different MR etiologies. Left ventricular outflow obstruction might occur due to retained native valve tissue. Paravalvular leaks might also pose a problem. There are 3 devices in development. The Endovalve- Herrmann prosthesis (Endovalve Inc., Princeton, New Jersey) (Fig. 13) is implanted from the LA side via a right mini-thoracotomy on a beating heart. The device is a foldable nitinol structure that attaches to the native valve with specially designed grippers, is fully valve sparing, and repositionable before release. Animal models have been successful, and a true percutaneous version is planned. The Lutter prosthesis, a nitinol stent-valve, has been implanted transapically in porcine models (46). The CardiAQ (CardiAQ Valve Technologies, Inc., Winchester, Massachusetts) prosthesis (Fig. 14) is in pre-clinical development and is delivered transseptally. Given the complexities involved with this approach, further improvements to these technologies will be required before clinical testing. Conclusions The field of percutaneous transcatheter MVR e is evolving exponentially. These emerging technologies can be classified by their site of action and device mechanism. The proposed classification is based on therapies aimed at the leaflets (leaflet plication, leaflet coaptation, leaflet ablation), annuloplasty (indirect: CS approach or asymmetrical approach; and direct: true percutaneous or hybrid), percutaneous chords, and LV remodeling. Percutaneous edge-to-edge leaflet repair has been shown to be noninferior to surgery in a randomized trial. Several other technologies including various direct and indirect annuloplasty and LV remodeling devices have achieved first-in-man results or are in preclinical testing. Most likely a combination of these technologies will be required for satisfactory MVR e. However, for many patients repair will not be possible, and MVR will be required. Although there are significant challenges, several percutaneous MVR prototypes are already in development. Reprint requests and correspondence: Dr. Carlos E. Ruiz, Lenox Hill Heart and Vascular Institute, 130 East 77th Street, New York, New York 10021. E-mail: cruiz@lenoxhill.net. REFERENCES 1. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a populationbased study. Lancet 2006;368:1005 11. 2. Iung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24:1231 43. 3. Bonow RO, Carabello BA, Chatterjee K, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease). J Am Coll Cardiol 2006;48:e1 148. 4. Enriquez-Sarano M, Schaff HV, Orszulak TA, Tajik AJ, Bailey KR, Frye RL. Valve repair improves the outcome of surgery for mitral regurgitation. A multivariate analysis. Circulation 1995;91:1022 8. 5. Suri RM, Schaff HV, Dearani JA, et al. Survival advantage and improved durability of mitral repair for leaflet prolapse subsets in the current era. Ann Thorac Surg 2006;82:819 26. 6. Gillinov AM, Wierup PN, Blackstone EH, et al. Is repair preferable to replacement for ischemic mitral regurgitation? J Thorac Cardiovasc Surg 2001;122:1125 41. 7. Fedak PW, McCarthy PM, Bonow RO. Evolving concepts and technologies in mitral valve repair. Circulation 2008;117:963 74.

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